tbuckley/cabot-search huggingface dataset:
Thrombospondin 1 missense alleles induce extracellular matrix protein aggregation and TM dysfunction in congenital glaucoma
Authors: Haojie Fu, Owen M. Siggs, Lachlan S.W. Knight, Sandra E. Staffieri, Jonathan B. Ruddle, Amy E. Birsner, Edward Ryan Collantes, Jamie E. Craig, Janey L. Wiggs, Robert J. D’Amato
Journal: Journal of Clinical Investigation (2022)

Glaucoma is a highly heritable disease that is a leading cause of blindness worldwide. Here, we identified heterozygous thrombospondin 1 (THBS1) missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma, a severe form of glaucoma affecting children. Thbs1R1034C-mutant mice had elevated intraocular pressure (IOP), reduced ocular fluid outflow, and retinal ganglion cell loss. Histology revealed an abundant, abnormal extracellular accumulation of THBS1 with abnormal morphology of juxtacanalicular trabecular meshwork (TM), an ocular tissue critical for aqueous fluid outflow. Functional characterization showed that the THBS1 missense alleles found in affected individuals destabilized the THBS1 C-terminus, causing protein misfolding and extracellular aggregation. Analysis using a range of amino acid substitutions at position R1034 showed that the extent of aggregation was correlated with the change in protein-folding free energy caused by variations in amino acid structure. Extracellular matrix (ECM) proteins, especially fibronectin, which bind to THBS1, also accumulated within THBS1 deposits. These results show that missense variants altering THBS1 p.Arg1034 can cause elevated IOP through a mechanism involving impaired TM fluid outflow in association with accumulation of aggregated THBS1 in the ECM of juxtacanalicular meshwork with altered morphology.
Is androgen receptor activity in metastatic prostate cancer a good biomarker for bipolar androgen therapy?
Authors: Nahuel Peinetti, Marijo Bilusic, Kerry L. Burnstein
Journal: Journal of Clinical Investigation (2022)

Androgen deprivation therapy (ADT) is the longstanding treatment for advanced prostate cancer (PC) because androgen receptor (AR) is the key therapeutic vulnerability for this disease. Bipolar androgen therapy (BAT) - the rapid cycling of supraphysiologic androgen (SPA) and low serum testosterone levels - is an alternative concept, but not all patients respond and acquired resistance can occur. In this issue of the JCI, Sena et al. developed a gene signature indicative of high AR activity to predict patient response to BAT, including a decline in both serum prostate-specific antigen (PSA) and tumor volume. Preclinical models showed that AR-mediated suppression of MYC, known to drive PC, was associated with decreased cell growth following SPA treatment. Because BAT eventually leads to resistance, the authors tested cycling between SPA and AR antagonism in a patient-derived xenograft and observed a delay in tumor growth. These findings represent a major step toward the informed use of BAT for advanced PC.
Temperature Trajectory Subphenotypes in Oncology Patients with Neutropenia and Suspected Infection
Authors: Nicole S. Benzoni, Kyle A. Carey, Alice F. Bewley, Jeff Klaus, Brian M. Fuller, Dana P. Edelson, Matthew M. Churpek, Sivasubramanium V. Bhavani, Patrick G. Lyons
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Despite etiologic and severity heterogeneity in neutropenic sepsis, management is often uniform. Understanding host response clinical subphenotypes might inform treatment strategies for neutropenic sepsis. Objectives: In this retrospective two-hospital study, we analyzed whether temperature trajectory modeling could identify distinct, clinically relevant subphenotypes among oncology patients with neutropenia and suspected infection. Methods: Among adult oncologic admissions with neutropenia and blood cultures within 24 hours, a previously validated model classified patients’ initial 72-hour temperature trajectories into one of four subphenotypes. We analyzed subphenotypes’ independent relationships with hospital mortality and bloodstream infection using multivariable models. Measurements and Main Results: Patients (primary cohort n = 1,145, validation cohort n = 6,564) fit into one of four temperature subphenotypes. “Hyperthermic slow resolvers” (pooled n = 1,140 [14.8%], mortality n = 104 [9.1%]) and “hypothermic” encounters (n = 1,612 [20.9%], mortality n = 138 [8.6%]) had higher mortality than “hyperthermic fast resolvers” (n = 1,314 [17.0%], mortality n = 47 [3.6%]) and “normothermic” (n = 3,643 [47.3%], mortality n = 196 [5.4%]) encounters (P < 0.001). Bloodstream infections were more common among hyperthermic slow resolvers (n = 248 [21.8%]) and hyperthermic fast resolvers (n = 240 [18.3%]) than among hypothermic (n = 188 [11.7%]) or normothermic (n = 418 [11.5%]) encounters (P < 0.001). Adjusted for confounders, hyperthermic slow resolvers had increased adjusted odds for mortality (primary cohort odds ratio, 1.91 [P = 0.03]; validation cohort odds ratio, 2.19 [P < 0.001]) and bloodstream infection (primary odds ratio, 1.54 [P = 0.04]; validation cohort odds ratio, 2.15 [P < 0.001]). Conclusions: Temperature trajectory subphenotypes were independently associated with important outcomes among hospitalized patients with neutropenia in two independent cohorts.
Reducing cardiovascular risk with immunomodulators: a randomised active comparator trial among patients with rheumatoid arthritis
Authors: Daniel H Solomon, Jon T Giles, Katherine P Liao, Paul M Ridker, Pamela M Rist, Robert J Glynn, Rachel Broderick, Fengxin Lu, Meredith T Murray, Kathleen Vanni, Leah M Santacroce, Shady Abohashem, Philip M Robson, Zahi Fayad, Venkatesh Mani, Ahmed Tawakol, Joan Bathon
Journal: Annals of the Rheumatic Diseases (2022)

Objective Recent large-scale randomised trials demonstrate that immunomodulators reduce cardiovascular (CV) events among the general population. However, it is uncertain whether these effects apply to rheumatoid arthritis (RA) and if certain treatment strategies in RA reduce CV risk to a greater extent. Methods Patients with active RA despite use of methotrexate were randomly assigned to addition of a tumour necrosis factor (TNF) inhibitor (TNFi) or addition of sulfasalazine and hydroxychloroquine (triple therapy) for 24 weeks. Baseline and follow-up 18 F-fluorodeoxyglucose-positron emission tomography/CT scans were assessed for change in arterial inflammation, an index of CV risk, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta. Results 115 patients completed the protocol. The two treatment groups were well balanced with a median age of 58 years, 71% women, 57% seropositive and a baseline disease activity score in 28 joints of 4.8 (IQR 4.0, 5.6). Baseline TBR was similar across the two groups. Significant TBR reductions were observed in both groups—ΔTNFi: −0.24 (SD=0.51), Δtriple therapy: −0.19 (SD=0.51)—without difference between groups (difference in Δs: −0.02, 95% CI −0.19 to 0.15, p=0.79). While disease activity was significantly reduced across both treatment groups, there was no association with change in TBR (β=0.04, 95% CI −0.03 to 0.10). Conclusion We found that addition of either a TNFi or triple therapy resulted in clinically important improvements in vascular inflammation. However, the addition of a TNFi did not reduce arterial inflammation more than triple therapy. Trial registration number NCT02374021 .
MSC based gene delivery methods and strategies improve the therapeutic efficacy of neurological diseases
Authors: Heng Zhou, Yan He, Wei Xiong, Shuili Jing, Xingxiang Duan, Zhiyun Huang, Gurek S. Nahal, Youjian Peng, Mingchang Li, Yaoqi Zhu, Qingsong Ye
Journal: Bioactive Materials (2022)

Mesenchymal stem cells (MSCs) are promising seed cells for neural regeneration therapy owing to their plasticity and accessibility. They possess several inherent characteristics advantageous for the transplantation-based treatment of neurological disorders, including neural differentiation, immunosuppression, neurotrophy, and safety. However, the therapeutic efficacy of MSCs alone remains unsatisfactory in most cases. To improve some of their abilities, many studies have employed genetic engineering to transfer key genes into MSCs. Both viral and nonviral methods can be used to overexpress therapeutic proteins that complement the inherent properties. However, to date, different modes of gene transfer have specific drawbacks and advantages. In addition, MSCs can be functionalized through targeted gene modification to facilitate neural repair by promoting neural differentiation, enhancing neurotrophic and neuroprotective functions, and increasing survival and homing abilities. The methods of gene transfer and selection of delivered genes still need to be optimized for improved therapeutic and targeting efficacies while minimizing the loss of MSC function. In this review, we focus on gene transport technologies for engineering MSCs and the application of strategies for selecting optimal delivery genes. Further, we describe the prospects and challenges of their application in animal models of different neurological lesions to broaden treatment alternatives for neurological diseases.
Effect of sport on health in people aged 60 years and older: a systematic review with meta-analysis
Authors: Juliana S Oliveira, Stephen Gilbert, Marina B Pinheiro, Anne Tiedemann, Liane Brito Macedo, Laísa Maia, Wing Kwok, Leanne Hassett, Catherine Sherrington
Journal: British Journal of Sports Medicine (2022)

Objectives To summarise evidence of benefits of sport for health among people aged 60+. Design Systematic review with meta-analysis of randomised controlled trials (RCTs). Data sources Medline, CINAHL, SPORTDiscus, the Physiotherapy Evidence Database from inception to April 2021. Study selection RCTs investigating the effect of sport on health-related outcomes in people aged 60+ compared with non-active control. Data synthesis and analysis Pooled effect sizes were calculated using random-effect models. Standardised mean differences (SMD), and mean difference (MD) were calculated. The Grading of Recommendations Assessment, Development and Evaluation system was used to assess the certainty of the evidence for analyses with ≥3 studies. Results Nine trials (628 participants) reported in 15 articles were included. Participation in sport improved cardiorespiratory fitness (n=5 trials; SMD=0.43, 95% CI 0.17 to 0.70; low certainty evidence), physical function (n=4; SMD=0.62, 95% CI 0.05 to 1.18; very low certainty evidence), and mental health (n=2; SMD=0.28, 95% CI 0.06 to 0.51) and reduced fat mass (n=6; MD=−0.99 kg, 95% CI −1.75kg to −0.23 kg; low certainty evidence) among older people. We found no significant effects of sport on overall physical activity participation, strength, balance, lean mass and bone mineral density (BMD). One study investigating quality of life reported a positive, but non-significant effect of sport. Conclusion Sport may have a positive impact on health outcomes in people aged 60+. There was uncertainty on the effect of sport on strength, balance, lean mass and BMD. Further research is needed to investigate the optimal type and dose of sport to maximise the long-term benefits among older people.
Massive Bilateral Coronary Air Embolism after Lung Biopsy
Authors: Jean Rabet, Cyril Sargentini, Corentin Aubourg, Sylvain Lemoine, Marie Sirima Marx, Emmanuel Rineau
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Massive Bilateral Coronary Air Embolism after Lung Biopsy." American Journal of Respiratory and Critical Care Medicine, 207(7), pp. 939–940
Maturation and abundance of tertiary lymphoid structures are associated with the efficacy of neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer
Authors: Xiaoyan Sun, Weiran Liu, Leina Sun, Huilan Mo, Yingnan Feng, Xinyi Wu, Chenguang Li, Chen Chen, Jingjing Li, Ying Xin, Zhenfa Zhang, Changli Wang, Bin Zhang, Dongsheng Yue
Journal: Journal for ImmunoTherapy of Cancer (2022)

Tertiary lymphoid structures (TLS) existence is correlated with favorable prognosis in many types of cancer including non-small cell lung cancer (NSCLC). However, TLS formation and its relationship with treatment response remains unknown in NSCLC who received anti-PD-1 antibody plus chemotherapy as the neoadjuvant treatment (neoadjuvant chemoimmunotherapy). Here, we investigate TLS maturation and abundance in resectable NSCLC receiving neoadjuvant treatments. We retrospectively collected formalin-fixed paraffin embedded (FFPE) tissues from patients with resectable NSCLC (stage II–IIIA) from three cohorts based on treatment: naïve (N=40), neoadjuvant chemoimmunotherapy (N=40), and neoadjuvant chemotherapy (N=41). The TLS in tumor tissues was detected by immunohistochemical staining, and the differences in TLS maturation and abundance among different treatment groups were analyzed, as well as the relationship with pathological response and prognosis of patients. Multiplex immunofluorescence staining was used to explore the features of immune microenvironment. Higher major pathological response (MPR) rate and pathological complete response (pCR) rate were in the neoadjuvant chemoimmunotherapy group than in the neoadjuvant chemotherapy group (MPR: 45.0% vs 17.1%; pCR: 35.0% vs 4.9%). Among the three cohorts, neoadjuvant chemoimmunotherapy-treated NSCLCs displayed highest TLS maturation and abundance. Both the maturation and abundance of TLS were significantly correlated with MPR in both the neoadjuvant chemoimmunotherapy and the chemotherapy group. Patients with high maturation and abundance of TLS exhibited better disease-free survival (DFS) in all the three cohorts. TLS maturation was also an independent predictor for DFS in the neoadjuvant chemoimmunotherapy and treatment naïve group. Multiplex immunohistochemistry analysis using paired biopsy-surgery samples showed increased infiltration of CD8+T cell and decreased infiltration of M1 and M2 macrophages after neoadjuvant chemoimmunotherapy treatment in patients achieving MPR. There were no significant differences in features of immune cell infiltration for those with mature TLS achieving MPR when cross-compared across the three cohorts. These results demonstrate that TLS maturation is associated with MPR and an independent predictor for DFS in resectable neoadjuvant chemoimmunotherapy-treated NSCLC. The induction of TLS maturation may be a potential mechanism of action of neoadjuvant chemoimmunotherapy in resectable NSCLC.
Morphological Differences between Patient Self-inflicted and Ventilator-induced Lung Injury: An Experimental Study
Authors: Pablo Cruces, Benjamín Erranz, Carlos González, Franco Diaz
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Morphological Differences Between Patient Self-inflicted and Ventilator-induced Lung Injury. An Experimental Study." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –
Somatic <i>TP53</i> mutations are preleukemic events in acute lymphoblastic leukemia
Authors: Guranda Chitadze, Anna Stengel, Cathrin John-Klaua, Julien Bruckmüller, Heiko Trautmann, Michaela Kotrova, Franziska Darzentas, Miriam Kelm, Karol Pal, Nikos Darzentas, Lorenz Bastian, Britta Kehden, Wiebke Wessels, Aeint-Steffen Ströh, Hans-Heinrich Oberg, Philipp M. Altrock, Constance Baer, Manja Meggendorfer, Nicola Gökbuget, Claudia D. Baldus, Claudia Haferlach, Monika Brüggemann
Journal: Blood (2022)
How We Manage Newly Diagnosed Multiple Myeloma With Circulating Tumor Cells
Authors: Niels W.C.J. van de Donk
Journal: Journal of Clinical Oncology (2022)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.Careful evaluation of peripheral blood for the presence of circulating plasma cells by morphologic assessment or by flow cytometric analysis is an essential component of the diagnostic workup in all patients with newly diagnosed multiple myeloma (MM) to timely differentiate between MM and primary plasma cell leukemia (pPCL), which is the most aggressive plasma cell dyscrasia. The improvement in survival over time is more modest in pPCL, compared with what has been achieved in MM. pPCL is currently defined by the presence of ≥ 5% circulating plasma cells. However, this cutoff is now challenged by new data, from three large cohorts of patients with newly diagnosed MM, showing that a threshold of 2% circulating tumor cells (CTCs) by flow cytometry can be used to identify a subset of patients with ultra-high-risk MM with comparable prognosis as patients with pPCL. These patients may benefit from more intensified first-line therapies, or from enrollment into specific clinical trials, designed for ultra-high-risk MM and pPCL. Apart from differentiating MM from pPCL, the quantification of CTCs is also useful for risk stratification in MM. The detection of CTCs above a threshold of 0.01%-0.07% (much lower than the threshold to define pPCL) appears to be an independent predictor of poor clinical outcomes in newly diagnosed MM. Additional studies, including transplant-ineligible patients or with incorporation of novel immunotherapies, are needed to identify a definitive prognostic CTC cutoff. The next step will be the incorporation of CTC detection into existing staging systems to improve risk stratification and treatment personalization.
Mental health symptoms are not correlated with peripheral inflammatory biomarkers concentrations in COVID-19-ARDS survivors
Authors: Dara Chean, Samuel Benarroch, Frédéric Pochard, Nancy Kentish-Barnes, Élie Azoulay, Matthieu Resche-Rigon, Bruno Megarbane, Danielle Reuter, Vincent Labbé, Alain Cariou, Guillaume Géri, Guillaume Meersch, Achille Kouatchet, Olivier Guisset, Fabrice Bruneel, Jean Reignier, Virginie Souppart, François Barbier, Laurent Argaud, Jean-Pierre Quenot, Laurent Papazian, Bertrand Guidet, Guillaume Thiéry, Kada Klouche, Olivier Lesieur, Alexandre Demoule, Christophe Guitton, Gilles Capellier, Bruno Mourvillier, Lucie Biard
Journal: Intensive Care Medicine (2022)
Effectiveness of mRNA-1273, BNT162b2, and BBIBP-CorV vaccines against infection and mortality in children in Argentina, during predominance of delta and omicron covid-19 variants: test negative, case-control study
Authors: Juan Manuel Castelli, Analia Rearte, Santiago Olszevicki, Carla Voto, María Del Valle Juarez, Martina Pesce, Agustina Natalia Iovane, Mercedes Paz, María Eugenia Chaparro, Maria Pia Buyayisqui, María Belén Markiewicz, Mariana Landoni, Carlos María Giovacchini, Carla Vizzotti
Journal: BMJ (2022)

Abstract Objective To estimate the effectiveness of a two dose vaccine schedule (mRNA-1273, BNT162b2, and BBIBP-CorV) against SARS-CoV-2 infection and covid-19 related death and short term waning of immunity in children (3-11 years old) and adolescents (12-17 years old) during periods of delta and omicron variant predominance in Argentina. Design Test negative, case-control study. Setting Database of the National Surveillance System and the Nominalized Federal Vaccination Registry of Argentina. Participants 844 460 c hildren and adolescents without previous SARS-CoV-2 infection eligible to receive primary vaccination schedule who were tested for SARS-CoV-2 by polymerase chain reaction or rapid antigen test from September 2021 to April 2022. After matching with their corresponding controls, 139 321 (60.3%) of 231 181 cases remained for analysis. Exposures Two dose mRNA-1273, BNT162b2, and BBIBP-CorV vaccination schedule. Main outcome measures SARS-CoV-2 infection and covid-19 related death. Conditional logistic regression was used to estimate the odds of SARS-CoV-2 infection among two dose vaccinated and unvaccinated participants. Vaccine effectiveness was estimated as (1–odds ratio)×100%. Results Estimated vaccine effectiveness against SARS-CoV-2 infection was 61.2% (95% confidence interval 56.4% to 65.5%) in children and 66.8% (63.9% to 69.5%) in adolescents during the delta dominant period and 15.9% (13.2% to 18.6%) and 26.0% (23.2% to 28.8%), respectively, when omicron was dominant. Vaccine effectiveness declined over time, especially during the omicron period, from 37.6% (34.2% to 40.8%) at 15-30 days after vaccination to 2.0% (1.8% to 5.6%) after ≥60 days in children and from 55.8% (52.4% to 59.0%) to 12.4% (8.6% to 16.1%) in adolescents. Vaccine effectiveness against death related to SARS-CoV-2 infection during omicron predominance was 66.9% (6.4% to 89.8%) in children and 97.6% (81.0% to 99.7%) in adolescents. Conclusions Vaccine effectiveness in preventing mortality remained high in children and adolescents regardless of the circulating variant. Vaccine effectiveness in preventing SARS-CoV-2 infection in the short term after vaccination was lower during omicron predominance and decreasing sharply over time. Trial registration National Registry of Health Research IS003720.
Viral dynamics during SARS-CoV-2 omicron infection highlight presymptomatic and asymptomatic infectiousness
Authors: Li Jiang, Lu Tang, Linyu Zhu, Yufang Zhu, Song Yang, Wenjie Chen, Yi Fan, Xuejiao Yang, Shuai Yang, Yulan Zheng, Yunsheng Xu, Peng Hong
Journal: Journal of Infection (2022)
The landscape of cancer-associated fibroblasts in colorectal cancer liver metastases
Authors: Ambre Giguelay, Evgenia Turtoi, Lakhdar Khelaf, Guillaume Tosato, Ikrame Dadi, Tommy Chastel, Marie-Alix Poul, Marine Pratlong, Stefan Nicolescu, Dany Severac, Antoine Adenis, Olivia Sgarbura-Popescu, Sébastien Carrère, Philippe Rouanet, François Quenet, Marc Ychou, Didier Pourqier, Pierre-Emmanuel Colombo, Andrei Turtoi, Jacques Colinge
Journal: Theranostics (2022)

Rationale: Patients with colorectal cancer die mainly due to liver metastases (CRC-LM).Although the tumor microenvironment (TME) plays an important role in tumor development and therapeutic response, our understanding of the individual TME components, especially cancer-associated fibroblasts (CAFs), remains limited.Methods: We analyzed CRC-LM CAFs and cancer cells by single-cell transcriptomics and used bioinformatics for data analysis and integration with related available single-cell and bulk transcriptomic datasets.We validated key findings by RT-qPCR, western blotting, and immunofluorescence.Results: By single-cell transcriptomic analysis of 4,397 CAFs from six CRC-LM samples, we identified two main CAF populations, contractile CAFs and extracellular matrix (ECM)-remodeling/pro-angiogenic CAFs, and four subpopulations with distinct phenotypes.We found that ECM-remodeling/pro-angiogenic CAFs derive from portal resident fibroblasts.They associate with areas of strong desmoplastic reaction and Wnt signaling in low-proliferating tumor cells engulfed in a stiff extracellular matrix.By integrating public single-cell primary liver tumor data, we propose a model to explain how different liver malignancies recruit CAFs of different origins to this organ.Lastly, we found that LTBP2 plays an important role in modulating collagen biosynthesis, ECM organization, and adhesion pathways.We developed fully human antibodies against LTBP2 that depleted LTBP2+ CAFs in vitro. Conclusion:This study complements recent reports on CRC-LM CAF heterogeneity at the single-cell resolution.The number of sequenced CAFs was more than one order of magnitude larger compared to existing data.LTBP2 targeting by antibodies might create opportunities to deplete ECM-remodeling CAFs in CRC-LMs.This might be combined with other therapies, e.g., anti-angiogenic compounds as already done in CRC.Moreover, we showed that in intrahepatic cholangiocarcinoma, in which ECM-remodeling CAF proportion is similar to that of CRC-LM, several genes expressed by ECM-remodeling CAFs, such as LTBP2, were associated with survival.